Protein synthesis is an indispensable process by which living organisms grow, differentiate, and propagate. The three stages of protein synthesis are initiation, elongation, and termination. In eukaryotes, the first event in protein synthesis is the attachment of a free molecule of methionine (Met) to the end of a tRNA. Met-tRNA and a small ribosomal RNA subunit 40S bind to the mRNA near the AUG initiation codon to form the 40S complex. Addition of the 60S ribosomal RNA subunit to the 40S complex forms the peptidyl-tRNA transfer site. Once the mRNA, 40S, and 60S complexes are in position, peptide synthesis may begin.
Translation initiation factors, eIF1a, eIF2, and eIF3, initiate the formation of the 40S complex and are part of the complex as well. Binding between the 40S ribosomal RNA subunit and the mRNA is aided by eIF4a, eIF4b, and eIF4f using energy from the hydrolysis of GTP bound to eIF2. Translation initiation factor eIF5 promotes the hydrolysis of ribosome-bound GTP producing the energy necessary to bind the 40S and 60S complexes.
eIF4f is a complex which recognizes 5'-mGpppN, the CAP structure of all eukaryotic mRNAs. The complex facilitates the association of the 40S subunit to mRNA for translation initiation. Translation initiation is regulated by the phosphorylation of the CAP-binding protein, eIF4e, a subunit of the eIF4f complex. Addition of insulin to adipocytes or muscle cells increases phosphorylation of eIF4e and stimulates initiation of protein synthesis (Morley, S. J. & Traugh, J. A. (1990) J. Biol. Chem. 265: 10611-10616). Overexpression of eIF4e has been associated with cell transformation (Lararis-Karatzas, A. et al. (1990) Nature 345: 544-547).
PHAS-I, PHAS-II, and 4E-BP1 are three regulators of translation initiation (Pause, A. et al. (1994) Nature 371: 762-767; Hu, C. et al. (1994) Proc. Natl. Acad. Sci. 91: 3730-3734; and Lin, T.-A. and Lawrence, J. C. Jr. (1996) J. Biol. Chem. 271: 30199-30204). The association of PHAS-I or 4E-BP1 with eIF4e prevents the formation of the active CAP-binding complex, eIF4f. Phosphorylation of PHAS-I or 4E-BP1 by an insulin- or a growth factor-dependent kinase releases eIF4e from a complex with PHAS-I or 4E-BP1 and prepares eIF4e to bind CAP for translation initiation. PHAS-I and PHAS-II are found to have overlapping but different patterns of expression in tissues. Phosphorylation of both PHAS proteins promotes dissociation of PHAS-eIF4e complexes and stimulates cell growth (Lin et al., supra).
The discovery of a new human translational regulator and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of inflammation and disorders associated with cell proliferation and apoptosis.